Second generation, orally active, antimalarial, artemisinin-derived trioxane dimers with high stability, efficacy, and anticancer activity

Ik Hyeon Paik, Suji Xie, Theresa A. Shapiro, Tanzina Labonte, Amy A. Narducci Sarjeant, Astrid C. Baege, Gary H. Posner

Research output: Contribution to journalArticlepeer-review

Abstract

In only two steps and in 63% overall yield, naturally occurring 1,2,4-trioxane artemisinin (1) was converted into C-10-carba trioxane conjugated diene dimer 4. This new dimer was then transformed easily in one additional 4 + 2-cycloaddition step into phthalate dimer 5, and further modification led to bis-benzyl alcohol dimer 7 and its phosphorylated analogues 8 and 9. Bis-benzyl alcohol dimer 7 is the most antimalarially active in vitro, 10 times more potent than artemisinin (1). Bis-benzyl alcohol dimer 7 is approximately 1.5 times more orally efficacious in rodents than the antimalarial drug sodium artesunate and is about 37 times more efficacious than sodium artesunate via subcutaneous administration. Both dimers 5 and 7 are thermally stable neat even at 60 °C for 24 h. Phthalate dimer 5 is very highly growth inhibitory but not cytotoxic toward several human cancer cell lines; both dimers 5 and 7 very efficiently and selectively kill human cervical cancer cells in vitro in a dose-dependent manner with no cytotoxic effects on normal cervical cells.

Original languageEnglish (US)
Pages (from-to)2731-2734
Number of pages4
JournalJournal of medicinal chemistry
Volume49
Issue number9
DOIs
StatePublished - May 4 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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